First Participants Dosed in Early Clinical Trial of Inhaled Therapy ARO-ENaC

A Phase 1/2 clinical trial assessing Arrowhead Pharmaceuticals‘ investigational inhaled therapy, ARO-ENaC, for the treatment of cystic fibrosis (CF), has dosed its first participants, the company announced.

The AROENaC1001 trial (NCT04375514) is designed to investigate ARO-ENaC in 24 healthy volunteers and 30 CF patients, and is currently recruiting participants.

In healthy people the goal is to determine the safety, tolerability, and pharmacokinetics (the movement of a drug into, through, and out of the body) of single ascending doses of ARO-ENaC. In CF patients, goals include safety, tolerability, and effectiveness of multiple ascending doses.

Whether ARO-ENaC also improves lung clearance and increases lung function, assessed via changes in forced expiratory volume (FEV1), also will be examined as exploratory measures.

“The Phase 1/2 clinical study, AROENaC1001, is designed to assess safety, tolerability, and pharmacokinetics and potentially provide an early assessment of efficacy in patients with CF,” Javier San Martin, MD, chief medical officer at Arrowhead, said in a press release.

“Our preclinical work on ARO-ENaC has been highly promising and we are eager to see how these results translate to humans,” Martin said.

ENaC is a sodium transport channel that is overactive in the lungs of people with CF. This increased activity contributes to dehydration and reduced mucus clearance in the lungs, leading patients to experience persistent lung infections, lung damage, and progressive loss of lung function.

ARO-ENaC is an investigational RNA therapy designed to lower the production of a piece of that sodium channel — the epithelial sodium channel alpha subunit (αENaC) — in the airways, thus lowering the amount of total ENaC.

Simply put, ARO-ENaC delivers a small interference RNA (RNAi) molecule to the lungs. This molecule is designed to bind the messenger RNA of αENaC and target it for destruction, preventing αENaC proteins from being made. (Messenger RNA is the intermediate molecule generated from DNA that works as a template for protein production.)

ARO-ENaC is Arrowhead’s first inhaled RNAi investigational therapy targeting the lungs. It was designed with the company’s proprietary Targeted RNAi Molecule (TRiM) platform, which enables tissue-specific delivery of RNAi therapies, and increases the extent and duration of gene silencing compared with other RNA interference approaches.

While ENaC has been studied extensively as a potential CF therapeutic target, inhaled therapies delivering small molecule inhibitors of this protein have seen their development limited by toxicity to the kidneys and short duration of action in the lungs.

ARO-ENaC, however, can durably target ENaC in the lungs, while avoiding negative effects on the kidneys. This treatment also was seen to double mucus clearance in healthy sheep and to preserve lung clearance in a sheep model of mucus obstruction, which supported the launch of the recent clinical trial.

“We believe ENaC, or epithelial sodium channel, is a target with great potential for many CF patients that may not be eligible for existing therapies due to their specific genotypes, commonly called class I patients, and for those that have an inadequate response to therapy,” Martin concluded.